Cocaine addiction is a devastating disorder and there are no truly effective treatments. All substance abuse disorders are associated with highly disrupted sleep patterns and circadian rhythms. It is clear that disrupted rhythms lead to an increased vulnerability for addiction and in turn chronic drug exposure further disrupts normal molecular and physiological rhythmicity over the light/dark cycle. However the mechanisms that underlie this association between disrupted circadian rhythms and addiction remain unclear. Over the last several years our lab and others have found that proteins that control circadian rhythms are intimately involved in the regulation of reward circuitry. These proteins directly influence dopaminergic signaling in the ventral tegmental area (VTA), nucleus accumbens (NAc) circuit. Furthermore, when these genes are disrupted specifically in this circuit, this changes the reward value and desire for cocaine. Some very exciting recent studies have discovered that these circadian proteins are directly connected to the metabolic state of the cell. The activity of these proteins changes with differences in the redox state which is determined largely by mitochondrial function. Cocaine is known to produce an increase in oxidative stress. It also alters the daily cellular redox balance which contributes to lasting behavioral plasticity. Given this tight association between cellular metabolism and circadian protein function, we hypothesize that cocaine-induced changes to the redox state of neurons in the NAc leads to altered circadian protein function and this is important in the regulation of drug reward. In this two year proposal we will focus on the interactions between two proteins which are important in the control of circadian rhythms, NPAS2 and Sirtuin 1(SIRT1). SIRT1's activity is dependent upon levels of NAD+ and thus changes to the redox state of the cell will alter the ability of NPAS2/SIRT1 to form an inhibitory complex which is crucial for proper circadian transcription. We will first determine the changes in the redox state of cells in the NAc over the light/dark cycl in mice exposed to chronic or acute cocaine. Second, we will determine how chronic or acute cocaine changes the association between NPAS2 and SIRT1 in the NAc, perhaps leading to complex formation at the wrong time of day. Finally, previous studies have found that SIRT1 activation leads to an increase in the preference for cocaine. We will determine if this is dependent upon its increased association with NPAS2. Taken together, this proposal will help determine the mechanistic link between chronic cocaine exposure, altered neuronal metabolism, and circadian protein function in the brain's reward circuit.